A significant body of work implicates a vascular contribution to the pathogenesis of late-life depression. However, the mechanisms underlying this relationship have not been clearly demonstrated. We propose that vascular pathology, characterized by impaired central vascular reactivity and cerebral hypoperfusion, may be the underlying contributor to the clinical, cognitive, and radiological findings in late-life depressio. The long-term goal of this line of research is to determine if decreased vascular reactivity and frontal hypoperfusion is associated with antidepressant nonremission. If correct, this will guide future studies to determine if pharmacological improvement of cerebral perfusion may be a valid antidepressant augmentation strategy. The rationale for this project is that in older populations, vascular disease is strongly associated with the development of depressive symptoms, cognitive deficits, and hyperintense lesions. Vascular pathology, such as decreased arterial lumens, reduced distensibility, and endothelial dysfunction result in the decreased ability of autoregulatory processes to maintain stable cerebral blood flow, resulting in cerebral hypoperfusion. Such perfusion deficits could contribute to antidepressant nonresponse as they would hinder improvements in dorsal system metabolism seen with antidepressant treatment. However, such individuals might receive benefit from approaches that improve cerebral perfusion. As the first step in this line of research, the objective of the current proposal is to determine if decreased vascular reactivity and frontal hypoperfusion in depressed elders predicts and persists with antidepressant nonremission. We will pursue our primary aim testing our hypothesis that decreased reactivity and hypoperfusion, specifically in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex, predict antidepressant nonremission. Our approach is to enroll 40 depressed elders who will complete clinical, cognitive, and MRI assessments before and after a 12-week open-label antidepressant trial of sertraline. Regional cerebral perfusion will be assessed using arterial spin labeling (ASL) at a) rest, b) during an emotional oddball task, and c) with a hypercarbic challenge to assess reactivity. This will allow us to examine if reduced reactivity and frontal perfusion is predictive of antidepressant nonremission. This proposal is innovative as it mechanistically examines how vascular dysregulation influences late-life depression outcomes. It is significant as it will improve our understanding of the pathogenesis of late-life depression and, if our hypotheses are correct, support studies examining the antidepressant properties of commercially available drugs that improve cerebral perfusion.